Oligomeric benzylsulfonium salts: Facile benzylation via high-load ROMP reagents

Article abstract of DOI:10.1021/jo0620260

(Chemical Equation Presented) The development of high-load, oligomeric benzylsulfonium salts, generated via ring-opening metathesis polymerization, and their utility in facile benzylations of various nucleophiles is reported. These oligomeric sulfonium salts exist as free-flowing powders and are stable at room temperature. After the benzylation event, purification is attained via simple dry load/filtration, followed by solvent removal to deliver products in excellent yield and purity.

Full text of DOI:10.1021/jo0620260

Oligomeric Benzylsulfonium Salts: Facile Benzylation via
High-Load ROMP Reagents
Mianji Zhang,† Daniel L. Flynn,*,‡ and Paul R. Hanson*,†
The Center for Chemical Methodologies and Library DeVelopment at the UniVersity of Kansas,
1501 Wakarusa DriVe, Lawrence, Kansas 66047, and Department of Chemistry, UniVersity of Kansas,
1251 Wescoe Hall DriVe, Lawrence, Kansas 66045-7582, Deciphera Pharmaceuticals, LLC,
4950 Research Park Way, Lawrence, Kansas 66047
phanson@ku.edu
ReceiVed September 30, 2006
The development of high-load, oligomeric benzylsulfonium salts, generated via ring-opening metathesis
polymerization, and their utility in facile benzylations of various nucleophiles is reported. These oligomeric
sulfonium salts exist as free-flowing powders and are stable at room temperature. After the benzylation
event, purification is attained via simple dry load/filtration, followed by solvent removal to deliver products
in excellent yield and purity.
Introduction
filtration is the sole purification protocol, are a testament to the
power of this approach that integrates synthesis and purification.
Despite huge advances in this area, limitations in nonlinear
reaction kinetics, low resin-load capacities, means of distributing
reagents, and facile access to designer resins continue to warrant
the development of new methods. One such method is the
general use of ring-opening metathesis polymerization (ROMP)
for generating high-load, immobilized reagents originally pio-
neered by Barrett and co-workers.3,4 Overall, the ability to
produce designer ROMP-derived polymers with tunable proper-
ties has now surfaced as a powerful technological advancement
in the arena of facilitated synthesis.
The recent growth of high-throughput screening for biologi-
cally active agents has placed a huge demand on efficient
generation of quality libraries comprised of novel structures.
This presents several challenges: increasing the speed in which
molecules can be made, ensuring the integrity of libraries
produced, and optimizing novelty of chemical space mapped
by each library. Traditional solid-phase organic synthesis (SPOS)
is undoubtedly a primary tool that has been utilized to address
this demand. While SPOS has its merits for offering a direct
purification technique and is highly amenable to automation, it
also presents limitations, such as low load levels of reactive
functionality in traditional solid-phase resins (typically 1 mmol/
g), poor reaction kinetics due to heterogeneity issues, and long
validation times in converting solution-phase protocols to SPOS
protocols.
One powerful approach to address these limitations is to
ultimately place the scaffold in solution while immobilizing the
reagent. In the context of this paradigm shift an array of
polymer-bound reagents and scavengers1 have appeared, ef-
fectively eliminating or circumventing the need for chromato-
graphic purifications, which typically is a bottleneck in synthetic
sequences.2 Recent successes in multistep total synthesis, using
exclusively immobilized reagents and scavengers, whereby
(1) (a) Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis 1997,
1217. (b) Booth, R. J.; Hodges, J. C. Acc. Chem. Res. 1999, 32, 18. (c)
Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.;
Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J.
Chem. Soc. Perkin Trans. 1 2000, 3815. (d) Kirschning. A.; Monenschein,
H.; Wittenberg, R. Angew. Chem., Int. Ed. 2001, 40, 650. (e) Yoshida, J.-
I.; Itami, K. Chem. ReV. 2002, 102, 3693. (f) van Heerbeek, R.; Kamer, P.
C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Chem. ReV. 2002, 102,
3717. (g) Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. ReV. 2002,
102, 3325. (h) Haag, R. Chem.-Eur. J. 2001, 7, 327. (i) Haag, R.; Sunder,
A.; Hebel, A.; Roller, S. J. Comb. Chem. 2002, 4, 112. (j) Bergbreiter. D.
E. Chem. ReV. 2002, 102, 3345. (k) Parlow, J. J. Curr. Opin. Drug DiscoV.
DeVel. 2005, 8, 757.
(2) (a) Baxendale, I. R.; Brusotti, G.; Matsuoka, M.; Ley, S. V. J. Chem.
Soc. Perkin Trans. 1 2002, 143. (b) Storer, R. I.; Takemoto, T.; Jackson, P.
S.; Brown, D. S.; Baxendale, I. R.; Ley, S. V. Chem.-Eur. J. 2004, 10,
2529. (c) Baxendale, I. R.; Ley, S. V.; Piutti, C. Angew. Chem., Int. Ed.
2002, 41, 2194. (d) Parlow, J. J.; Flynn, D. L. Tetrahedron 1998, 54, 4013.
† University of Kansas and KU-CMLD.
‡ Deciphera Pharmaceuticals, LLC and KU-CMLD.
10.1021/jo0620260 CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/04/2007
3194
J. Org. Chem. 2007, 72, 3194-3198

ROMP-DeriVed Oligomeric Benzylsulfonium Salts
SCHEME 1
Previously, we have used ROMP in the development of
several high-load, soluble oligomeric sulfonate ester reagents,
which effectively serve as facile benzylating agents for a series
of cyclic secondary amines.5 We now report a number of high-
load, oligomeric sulfonium salts (2GOBSPcn)6 that can be readily
prepared and offer a wider versatility to the types of nucleophiles
they can benzylate. These include secondary amines, phenols,
benzenethiols and 2-mercapto-benzimidazoles.
Sulfonium salts have been widely employed in organic
synthesis. Prominent among the uses of such salts are their
conversion into sulfonium ylides for use in the Corey epoxi-
dation procedure7 and for alkylation of nucleophiles. Examples
of the latter include reactions with azide ion,8 carboxylates,9
nucleosides,10 phenols and thiophenols,11 amines,12 cyanides,13
amides,14 enolates,15 and sulfenates.16 Application in Pd-
catalyzed carbon-carbon formations has also been reported.17
With this versatility in mind, we set out to develop an oligomeric
benzylsulfonium salt with applications in benzylation of a series
of nucleophiles.
TABLE 1. Sulfonium Salt Monomers and Oligomers23
Ar
monomer 5 ROM Polymer 7 theoretical load (mmol/g)
Ph
5a, 96%
7a (n ) 50), 97%
(n ) 10), 96%
2.9
2.8
2.9
2.9
2.6
2.6
2.8
2.4
Results and Discussion
(n ) 30), 98%
OBSPc (oligomeric benzylsulfonium perchlorate) can be
synthesized using a simple 5-step process starting from com-
mercially available anhydride 1 (Scheme 1). Reduction of 1 with
lithium aluminum hydride in THF gave diol 2 in high yield
(95%).18 Diol 2 was subsequently treated with methanesulfonyl
chloride to produce bismesylate 3 in high yield (83%). Nor-
bornenyl-tagged sulfide 419 was obtained from reaction of 3
with sodium sulfide in the presence of aliquate 336 in a mixed
(n ) 100), 99%
7b (n ) 50), 94%
7c (n ) 50), 96%
7d (n ) 50), 92%
7e (n ) 50), 99%
3-Cl-Ph
4-Cl-Ph
3-Me-Ph
4-CF3-Ph
5b, 90%
5c, 75%
5d, 90%
5e, 86%
solvent of toluene and water. Benzylation20 of sulfide 4 with
various benzyl bromides in the presence of 1 equiv of sodium
perchlorate afforded monomers 5 in good to excellent yield (75-
96%). Subsequent ROM polymerization with (IMesH2)(PCy3)-
(Cl)2RuCHPh [cat-6]21 yielded 2GOBSPcn of differing lengths
(n) depending upon the mol % of the catalyst used. Quenching
of ROM polymerization with ethyl vinyl ether, followed by
filtration, provided various oligomeric variants of OBSPc in
excellent yields (92-99%) (Table 1). All exist as free-flowing
solids with theoretical load values of 2.4-2.9 mmol/g.22 These
oligomers can be isolated and stored at room temperatures for
long periods of time.
(3) (a) Barrett, A. G. M.; Hopkins, B. T.; Ko¨bberling, J. Chem. ReV.
2002, 102, 3301. (b) Flynn, D. L.; Hanson, P. R.; Berk, S. C.; Makara, G.
M. Curr. Opin. Drug DiscoV. DeVel. 2002, 5, 571. (c) Harned, A. M.; Probst,
D. A.; Hanson, P. R. The Use of Olefin Metathesis in Combinatorial
Chemistry: Supported and Chromatography-Free Syntheses. In Handbook
of Metathesis; Grubbs, R. H., Ed.: Wiley-VCH: Weinheim, 2003; Vol. 2,
pp 361.
(4) (a) Harned, A. M.; Zhang, M.; Vedantham, P.; Mukherjee, S.; Herpel,
R. H.; Flynn, D. L.; Hanson, P. R. Aldrichim. Acta 2005, 38, 3. (b) Barrett,
A G. M.; Bibal, B.; Hopkins, B. T.; Koebberling, J.; Love, A. C.; Tedeschi,
L. Tetrahedron 2005, 61, 12033. (c) Harned, A. M.; Sherrill, W. M.; Flynn,
D. L.; Hanson, P. R. Tetrahedron 2005, 61, 12093.
We initially followed an approach developed by Matsuyma
and co-workers,15d,e in which longer reaction times (3 days) were
required. Test reactions of different lengths of oligomer 7a with
N-methylaniline revealed the 50-mer as the best benzylation
oligomer. The use of 2GOBSPc50 (7a) in the benzylation of an
(5) Zhang, M.; Moore, J. D.; Flynn, D. L.; Hanson, P. R. Org. Lett.
2004, 6, 2657.
(6) 2GOBPScn stands for oligomeric benzylsulfonium perchlorate of n-mer
length (n ) 10, 30, 50, 100) prepared by ROMP of monomer sulfonium
salts 5 using the second generation Grubbs catalyst 6.
(7) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 3782.
Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(8) Hoffmann, H. M. R.; Hughes, E. D. J. Chem. Soc. 1964, 1259.
(9) Lewis, T. R.; Archer, S. J. Am. Chem. Soc. 1951, 73, 2109.
(10) Yamauchi, K.; Hisanaga, Y.; Kinoshita, M. Synthesis 1980, 852.
(11) Forrester, J.; Jones, R. V. S.; Newton, L.; Preston, P. N. Tetrahedron
2001, 57, 2871.
(12) Badet, B.; Julia, M.; Ramirez-Munoz, M. Synthesis 1980, 926.
(13) Badet, B.; Julia, M.; Lefevre, C. Bull. Soc. Chim. Fr. 1984, 431.
(14) Julia, M.; Mestdagh, H. Tetrahedron 1983, 39, 443.
(15) (a) Garst, M. E.; McBride, B. J. J. Org. Chem. 1983, 48, 1362. (b)
Kobayashi, M.; Umemura, K.; Watanabe, N.; Matsuyama, H. Chem. Lett.
1985, 1067. (c) Kobayashi, M.; Umemura, K.; Matsuyama, H. Chem. Lett.
1987, 327. (d) Umemura, K.; Matsuyama, H.; Watanabe, N.; Kobayashi,
M.; Kamigata, N. J. Org. Chem. 1989, 54, 2347. (e) Umemura, K.;
Matsuyama, H.; Kamigata, N. Bull. Chem. Soc. Jpn. 1990, 63, 2593.
(16) Kobayashi, M.; Manabe, K.; Umemura, K.; Matsuyama, H. Sulfur
Lett. 1987, 6, 19.
(19) Bloch, R.; Abecassis, J. Tetrahedron Lett. 1982, 23, 3277.
(20) Aggarwal, V. K.; Thompson, A.; Jones, R. V. H. Tetrahedron Lett.
1994, 35, 8659.
(21) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(22) The actual load of reagent 7a (n ) 50) was experimentally
determined to be 2.7-2.8 mmol/g utilizing 1H NMR to measure the product
of benzylation of excess 1-phenylpiperazine with 7a (n ) 50) in DCM
using DMF as an internal standard.
(23) We have previously found that there is a good correlation between
the mol % of Grubbs catalyst added and the Gaussian distribution of
oligomers formed, which is the case with OBSPc. We have made these
reagents several times with good reproducibility and consistency. MALDI-
TOF and/or GPC data is normally attained on all oligomers; however, both
methods have failed to give good results for our previously published
reactive oligomeric bis-acid chloride (OBAC) and sulfonyl chloride resin
(OSC).
(17) (a) Srogl, J.; Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc.
1997, 119, 12376. (b) Zhang, S.; Marshall, D.; Liebeskind, L. S. J. Org.
Chem. 1999, 64, 2796. (c) Vanier, C.; Lorge´, F.; Wagner, A.; Mioskowski,
C. Angew. Chem., Int. Ed. 2000, 39, 1679.
(18) Lok, K. P.; Jakovac, I. J.; Jones, J. B. J. Am. Chem. Soc. 1985,
107, 2521.
(24) (a) Purification of final compounds was carried out using a SiO2
SPE (∼1 g) and eluting with 6 mL of EtOAc. (b) Purities were determined
1
by GC and confirmed by H NMR. (c) Yields were calculated from pure
products after SPE purification.
J. Org. Chem, Vol. 72, No. 9, 2007 3195

Zhang et al.
TABLE 2. Benzylation of Nucleophiles with Reagent 7a in CH2Cl2
at Room Temperature24
TABLE 4. Benzylation of 1-Phenylpiperazine with Reagents 7 (1.2
Equiv) in CH2Cl2 at 80 °C in a Sealed Vial24
TABLE 3. Benzylation of Nucleophiles with Reagent 7a in Ionic
Liquid [(Bmim)PF6]24
temp time yield purity
entry
Nu-H
Nu-Bn
(°C)
(h)
(%)
(%)
with excellent yields (Table 4). It is noteworthy that only 1.2
equiv of reagent was required to carry out the reaction.
Benzylations were equally effective with benzyl systems
substituted with both electron-withdrawing (Table 4, entries 2,
3, and 5) and electron-donating groups (Table 4, entry 4).
1
2
3
4
PhNHMe
PhNHMe
Et2NH
PhN(Me)Bn 8a
PhN(Me)Bn 8a
Et2NBn 8c
25
50
50
50
72
2
2
80
93
82
82
95
95
93
94
p-BrPhSH p-BrPhSBn 9
2
We next examined the benzylation of other secondary amines
using the simple benzylating agent 7a (n ) 50). Over the course
of this study, it was found that cyclic secondary amines were
easily benzylated in this process in comparison to acyclic
secondary amines, which required a longer reaction time. The
results of the benzylation of these scaffolds, using the identical
procedure described as above, led to the corresponding tertiary
amines 8a-c and 11a-e in good to excellent yields and purities
as outlined below in Table 5.
array of nucleophiles, such as secondary amines and phenol,
produced promising results (Table 2), although the method
required a large excess of reagent 7a (8 equiv) in order to
complete the reactions. Nonetheless, benzylated products 8 were
obtained with high yield and purity using precipitation/filtration
as the sole purification protocol.
In order to improve this protocol, we next studied the
benzylation of secondary amines and benzenethiol with
2GOBSPc50 (7a) in an ionic liquid [(Bmim)PF6]. After the
benzylation event, the reaction mixture was partitioned between
hexanes and the ionic liquid. Good yields and excellent purities
were obtained after evaporation of the solvent (Table 3). The
results show that the ionic liquid [(bmim)PF6] facilitated the
benzylating event (3 vs 8 equiv of 7a used) and occurred with
shortened reaction times when carried out at 50 °C. Although
an improvement in some respects, the use of nonpolar solvents
such as hexanes severely limited the ionic liquid variant of the
method.
Benzylation of phenols and thiophenol were similarly inves-
tigated. Variable phenols and benzenethiol were also benzylated
with oligomer 7a (n ) 50) using the procedure described above
to deliver the ethers (8e, 12a-f) and thioether (9) in good to
excellent yields and purities (Table 6, entries 1-8). Finally,
various 2-mercaptobenzimidazoles were benzylated under the
same condition using reagent 7a (n ) 50) (Table 6, entries
9-11) in good yields and purities.
In conclusion, we have demonstrated the first synthesis and
utilization of ROMP-derived oligomeric sulfonium salts as
benzylating agents. These entities proved extremely efficient
in the benzylation of cyclic and acyclic secondary amines,
phenols, thiophenols, and 2-mercaptobenzimidazoles. Benzyl-
ation of primary amines such as aniline gave a mixture of mono-
and dibenzylated products. Purifications following the benzyl-
ation reaction were carried out via simple filtration, which
exploits inherent polarity of oligomers produced via ROMP.
Efforts to widen the scope of these reagents, preparation of more
diversified reagents as well as extension into library synthesis
are underway. The results of these endeavors will be reported
in due course.
With this limitation in mind, we therefore developed an
improved procedure for benzylation with OBSPc, employing
CH2Cl2 as solvent, Cs2CO3 as base, NaI as an additive, and
using higher temperatures (80 °C) in a sealed vial. 1-Phenylpip-
erazine was selected as a substrate and was subsequently treated
with different benzyl variants of reagent 7. Thus, a mixture of
1-phenylpiperazine (1 equiv), reagent 7 (1.2 equiv), Cs2CO3 (1.2
equiv), and NaI (15 mol %) in CH2Cl2 was heated to 80 °C in
a sealed vial. After stirring for 1 h at 80 °C, silica gel was added
to the reaction mixture and the solvent was removed. Simple
loading of the residue on a SiO2 SPE and elution with EtOAc
afforded pure product. This method exploits inherent polarity
of the oligomers produced via ROMP to yield pure products
3196 J. Org. Chem., Vol. 72, No. 9, 2007

ROMP-DeriVed Oligomeric Benzylsulfonium Salts
TABLE 5. Benzylation of Secondary Amines with Reagent 7a in
TABLE 6. Benzylation of Phenols, Benzenethiols, and
2-Mercaptobenzimidazoles with Reagent 7a in Ch2Cl2 at 80 °C in a
Sealed Vial24
CH2Cl2 at 80 °C in a Sealed Vial24
Experimental Section
Reduction of cis-5-Norbornene-endo-2,3-dicarboxylic Anhy-
dride 1.25 Anhydride 1 (10.0 g, 61 mmol) was reduced with LiAIH4
(4.32 g, 122 mmol) in THF (200 mL) at room temperature (RT)
for 5.5 h. Nonaqueous workup and solvent removal gave cis-endo-
2,3-bis(hydroxymethyl) bicyclo[2.2.1]hept-5-ene (2, 8.97 g, 95%
yield); 1H NMR 1.40 (t, J ) 1.0 Hz, 2H), 6.02 (t, J ) 1.8 Hz, 2H),
4.07 (br s, 2H), 3.61 (dd, J ) 3.5, 11.2 Hz, 2H), 3.39-3.30 (m,
2H), 2.78 (t, J ) 1.5 Hz, 2H), 2.55-2.47 (m, 2H), 1.42-1.35 (m,
2H); 13C NMR 134.7, 63.4, 49.9, 46.5, 45.0.
3.26-3.13 (m, 2H), 2.75 (br s, 2H), 2.71-2.62 (m, 2H), 2.41-
2.32 (m, 2H), 1.78 (dt, J ) 1.7, 8.2 Hz, 1H), 1.72 (dd, J ) 0.4, 8.2
Hz, 1H); 13C NMR 137.0, 55.1, 54.0, 45.5, 34.5.
Preparation of Bismesylate 3. To a solution of diol 2 (4.13 g,
26.78 mmol) and Et3N (10.84 g, 107.13 mmol, 15 mL) in CH2Cl2
was added dropwise methanesulfonyl chloride (12.27 g, 107.13
mmol, 8.3 mL) at 0 °C under Ar over 10 min. The mixture was
stirred at 0 °C under Ar for 2 h; H2O (40 mL) was added dropwise
at 0 °C to quench the reaction. The organic layer was separated,
and the aqueous layer was extracted with CHCl3 (2 × 30 mL).
The combined organic layers were washed with H2O (20 mL) and
brine (20 mL) and dried (MgSO4). The solvent was removed under
reduced pressure, Et2O was added to the residue, and a yellow solid
was formed and washed with additional Et2O to obtain pure
General Procedure for Preparation of Norborene-Tagged
Sulfonium Perchlorate Monomers 5.27 Sulfide (1 equiv), benzyl
bromide (1 equiv), and NaClO4‚H2O (1 equiv) were stirred in a
minimum amount of acetone at RT until no further sulfide remained.
The salt (NaBr) was filtered off and washed with a minimum
amount of acetone. The resulting filtrate was evaporated under
reduced pressure and triturated with Et2O to yield crude sulfonium
salt monomer 5a-e, which was further washed with Et2O twice to
afford sulfonium salts 5a-e as mixtures of sulfur diastereoisomers
with ratios varying between 1:1 and 6:1.
1
bismesylate 3 (6.91 g, 83%). H NMR 6.24 (d, J ) 1.7 Hz, 2H),
5a: sulfide 4 (1.470 g, 9.65 mmol), benzyl bromide (1.651 g,
9.65 mmol, 1.15 mL), and NaClO4‚H2O (1.356 g, 9.65 mmol) were
stirred in acetone (8 mL). 3.170 g (96%) of 5a was obtained as
4.04-4.00 (m, 2H), 3.95-3.88 (m, 2H), 3.04-2.96 (m, 8H), 2.73-
2.64 (m, 2H), 1.60 (dd, J ) 1.8, 7.0 Hz, 1H), 1.40 (d, J ) 8.6 Hz,
1H); 13C NMR 135.5, 69.6, 49.0, 45.5, 41.2, 37.3.
1
Synthesis of Norbornenyl-Tagged Cyclic Sulfide 4.26 A mixture
of bismesylate 3 (19.00 g, 61.2 mmol), Na2S‚9H2O (19.11 g, 79.6
mmol), and Aliquate-336 (4.95 g, 12.2 mmol) in a mixed solvent
of toluene (100 mL) and H2O (100 mL) was stirred and heated to
90 °C overnight. The organic portion was separated and the aqueous
layer was extracted with EtOAc (3 × 50 mL). The combined
organic layers were washed with water and brine, dried (MgSO4),
and concentrated under reduced pressure. The residue was purified
by column chromatograph (10% EtOAc in hexanes) to obtain 8.41
white solid (∼1/1 mixture). H NMR major: 7.52-7.33 (m, 5H),
6.35 (t, J ) 1.9 Hz, 2H), 4.66 (s, 2H), 3.75-3.56 (m, 3H), 3.19-
3.06 (m, 2H), 2.99 (br s, 2H), 1.77-1.60 (m, 3H); minor: 7.52-
7.33 (m, 5H), 5.90 (t, J ) 1.8 Hz, 2H), 4.73 (s, 2H), 3.75-3.56
(m, 3H), 3.19-3.06 (m, 2H), 2.90 (br s, 2H), 2.39 (dd, J ) 11.8,
10.0 Hz, 2H), 1.77-1.60 (m, 1H); 13C NMR 137.8, 136.9, 131.7,
130.34, 130.30, 130.0, 129.7, 129.4, 128.2, 125.8, 54.9, 53.2,
50.7,47.0, 46.9, 46.5, 46.3, 45.1, 44.2, 41.4; HRMS (EI) calcd for
M+ (C16H19S) required 243.1208, found 243.1197.
1
5b: sulfide 4 (200 mg, 1.31 mmol), 3-chloro-benzyl bromide
(270 mg, 1.31 mmol, 172 µL), and NaClO4‚H2O (185 mg, 1.31
g of cyclic sulfide 4 (90%). H NMR 6.18 (t, J ) 1.8 Hz, 2H),
(25) Lok, K. P.; Jakovac, I. J.; Jones, J. B. J. Am. Chem. Soc. 1985,
107, 2521.
(26) Bloch, R.; Abecassis, J. Tetrahedron Lett. 1982, 23, 3277.
(27) Aggarwal, V. K.; Thompson, A.; Jones, R. V. H. Tetrahedron Lett.
1994, 35, 8659.
J. Org. Chem, Vol. 72, No. 9, 2007 3197

Zhang et al.
mmol) were stirred in acetone (1 mL). 443 mg (90%) of 5b was
7a (XdH, n ) 10): 5a (100 mg, 0.29 mmol) and catalyst 6 (25
mg, 0.029 mmol) in CH2Cl2 (5 mL) was refluxed for 3.5 h to give
99 mg of a light-tan-colored free-flowing solid (96%).
7a (X ) H, n ) 30): 5a (252 mg, 0.73 mmol) and catalyst 6
(21 mg, 0.024 mmol) in CH2Cl2 (7 mL) was refluxed for
3.5 h to give 248 mg of a light-tan-colored free-flowing solid
(98%).
7a (X ) H, n ) 100): 5a (228 mg, 0.665 mmol) and catalyst 6
(5.6 mg, 0.006 mmol) in CH2Cl2 (6 mL) was refluxed for 3.5 h to
give 227 mg of a tan-colored free-flowing solid (99%).
7b (X ) 3-Cl, n ) 50): 5b (443 mg, 1.17 mmol) and catalyst
6 (20 mg, 0.023 mmol) in CH2Cl2 (13 mL) was refluxed for 5 h to
give 418 mg light-tan-colored free-flowing solid (94%).
7c (X ) 4-Cl, n ) 50): 5c (369 mg, 0.98 mmol) and catalyst 6
(17 mg, 0.02 mmol) in CH2Cl2 (10 mL) was refluxed for 3.5 h to
give 353 mg of a light-tan-colored free-flowing solid (96%).
7d (X ) 3-Me, n ) 50): 5d (415 mg, 1.16 mmol) and catalyst
6 (20 mg, 0.023 mmol) in CH2Cl2 (12 mL) was refluxed for 3.5 h
to give 380 mg of a light-tan-colored free-flowing solid (92%).
7e (X ) 4-CF3, n ) 50): 5e (350 mg, 0.85 mmol) and catalyst
6 (14 mg, 0.017 mmol) in CH2Cl2 (10 mL) was refluxed for
9.5 h to give 350 mg of a light-tan-colored free-flowing solid
(99%).
1
obtained as white solid (∼5/1 mixture). H NMR major: 7.49-
7.29 (m, 4H), 6.37 (t, J ) 1.8 Hz, 2H), 4.66 (s, 2H), 3.80-3.58
(m, 3H), 3.23-3.09 (m, 2H), 3.01 (br s, 2H), 1.74-1.64 (m, 2H),
1.62 (br s, 1H); minor: 7.49-7.29 (m, 4H), 6.05 (t, J ) 1.8 Hz,
2H), 4.75 (s, 2H), 3.80-3.58 (m, 3H), 3.23-3.09 (m, 2H), 2.96
(br s, 2H), 1.74-1.64 (m, 2H), 1.62 (br s, 1H); 13C NMR (CD3-
COCD3) 138.6, 138.3, 135.6, 135.5, 132.7, 132.2, 132.1, 131.4,
131.1, 130.9, 130.7, 130.0, 129.99, 55.3, 54.4, 54.3, 51.59, 51.53,
48.6, 47.4, 47.3, 46.1, 45.8, 44.8, 44.1; HRMS (EI) calcd for M+
(C16H18ClS) required 277.0818, found 277.0817.
5c: sulfide 4 (200 mg, 1.31 mmol), 4-chloro-benzyl bromide (270
mg, 1.31 mmol), and NaClO4‚H2O (185 mg, 1.31 mmol) were
stirred in acetone (1 mL). 370 mg (75%) of 5c was obtained as
white solid (∼2/1 mixture). 1H NMR (CD3COCD3) major: 7.75-
7.56 (m, 2H), 7.56-7.43 (m, 2H), 6.42 (br s, 2H), 4.79 (s, 2H),
3.93-3.76 (m, 2H), 3.70 (dd, J ) 13.8, 7.5 Hz, 2H), 3.25 (dd, J )
13.4, 5.0 Hz, 2H), 3.13-2.88 (m, 2H), 1.84-1.61 (m, 2H); minor:
7.75-7.56 (m, 2H), 7.56-7.43 (m, 2H), 6.25 (br s, 2H), 4.91 (s,
2H), 3.93-3.76 (m, 2H), 3.70 (dd, J ) 13.8, 7.5 Hz, 2H), 3.25
(dd, J ) 13.4, 5.0 Hz, 2H), 3.13-2.88 (m, 2H), 1.84-1.61 (m,
2H); 13C NMR (CD3COCD3) 138.5, 138.3, 136.5, 136.2, 133.9,
133.2, 130.5, 130.4, 129.2, 127.8, 55.3, 54.3, 51.5, 48.5, 47.4, 47.2,
44.6, 43.8; HRMS (EI) calcd for M+ (C16H18ClS) required
277.0818, found 277.0817.
5d: sulfide 4 (200 mg, 1.31 mmol), 3-methy-benzyl bromide
(242 mg, 1.31 mmol), and NaClO4‚H2O (185 mg, 1.31 mmol) were
stirred in acetone (1 mL). 420 mg (90%) of 5d was obtained as a
white solid (∼3/1 mixture). 1H NMR (CD3COCD3) major: 7.51-
7.21 (m, 4H), 6.41 (t, J ) 1.8 Hz, 2H), 4.73 (s, 2H), 3.90-3.75
(m, 2H), 3.67 (dd, J ) 14.2, 8.0 Hz, 2H), 3.21 (dd, J ) 14.2, 6.0
Hz, 2H), 3.05 (br s, 2H), 2.34 (s, 3H), 1.74-1.64 (m, 2H); minor:
7.51-7.21 (m, 4H), 6.14 (t, J ) 1.8 Hz, 2H), 4.83 (s, 2H), 3.90-
3.75 (m, 2H), 3.36-3.26 (m, 2H), 3.00 (br s, 2H), 2.67 (m, 2H),
2.38 (s, 3H), 1.82-1.75 (m, 2H); 13C NMR (CD3COCD3) 140.3,
140.2, 138.5, 138.1, 132.8, 131.8, 131.6, 131.4, 130.4, 130.2, 130.1,
129.4, 128.4, 128.3, 55.2, 54.4, 51.6, 48.4, 47.3, 47.2, 46.5, 46.4,
44.4, 43.3, 21.3; HRMS (EI) calcd for M+ (C17H21S) required
257.1364, found 257.1358.
5e: sulfide 4 (152 mg, 1.00 mmol), 4-trifluoromethyl-benzyl
bromide (239 mg, 1.00 mmol), and NaClO4‚H2O (140 mg, 1.00
mmol) were stirred in acetone (1 mL). 352 mg (86%) of 5e was
obtained as a white solid (∼6/1 mixture). 1H NMR major: 7.70-
7.55 (m, 4H), 6.37 (t, J ) 1.8 Hz, 2H), 4.76 (s, 2H), 3.80-3.60
(m, 4H), 3.16 (br d, J ) 12.4 Hz, 2H), 3.01 (br s, 2H), 1.74-1.64
(m, 3H); minor: 7.70-7.55 (m, 4H), 6.07 (t, J ) 1.8 Hz, 2H),
4.86 (s, 2H), 3.80-3.60 (m, 4H), 3.16 (br d, J ) 12.4 Hz, 2H),
2.96 (br s, 2H), 1.74-1.64 (m, 3H); 13C NMR (CD3COCD3) 138.6,
138.3, 135.1, 132.4, 132.3, 132.0, 127.3 (q, J ) 4.1 Hz), 126.4,
123.7, 54.4, 51.7, 51.6, 48.6, 47.4, 47.3, 45.8, 45.0, CF3 missed
because of highly coupled; HRMS (EI) calcd for M+ (C17H18F3S)
required 311.1081, found 311.1071.
ROMP Procedure for the Generation of the Oligomeric
Benzylsulfonium Perchlorates 7 (2GOBSPcn). In a round-bottom
flask, sulfonium perchlorate 5 was dissolved in degassed (argon)
CH2Cl2. To this solution was added the second generation Grubbs
metathesis catalyst 6 in one portion. The reaction was refluxed under
argon and a precipitate was formed immediately. Once the
polymerization was complete (3.5-9.5 h), the reaction was
quenched by the addition of ethyl vinyl ether (EVE). The precipitate
was filtrated and washed with copious amounts of CH2Cl2 to furnish
2GOBSPcn as a light-tan-colored free-flowing solid.
General Procedure for Benzylation Using 2GOBSPcn in
CH2Cl2 at RT. A mixture of nucleophile (0.06 mmol), 2GOBSPcn
(8.0 equiv), and anhydrous K2CO3 (8 equiv) was stirred in dry CH2-
Cl2 (2 mL) at RT for 3 days. EtOAc (5 mL) was added to precipitate
the oligomeric sulfide. After filtration of insoluble materials, the
filtrate was concentrated to dryness. The residue was passed through
a SiO2 SPE to afford benzylated products 8a-e in high yield and
purities (see Tables 2).
General Procedure for Benzylation Using 2GOBSPc50 in An
Ionic Liquid. A mixture of nucleophile (0.06 mmol), 2GOBSPcn
(2.4-3.0 equiv), and anhydrous K2CO3 (2.4-3.0 equiv) was stirred
in (Bmim)PF6 (1 mL) at RT for 3 days or heated at 50 °C for 2-4
h. Hexane (2 mL) was added to separate the required product from
the oligomers, inorganic salts, and ionic liquid. The hexane layer
was concentrated and the residue was passed through a SiO2 SPE
to afford benzylated products 8a,c and 9 in high yield and purities
(see Tables 3).
General Procedure for Benzylation Using 2GOBSPc50 in
CH2Cl2 at 80 °C. A mixture of nucleophile (0.05 mmol), 2GOBSPcn
(1.2 equiv), anhydrous Cs2CO3 (1.2 equiv), and NaI (0.15 equiv)
was stirred in CH2Cl2 (1 mL) and heated at 80 °C in a sealed vial
for 1-3 h. Silica gel (150 mg) was added to the reaction mixture,
and the solvent was removed under reduced pressure. The residue
was then loaded on a SiO2 SPE and eluted with EtOAc to afford
pure benzylated products 8a-e, 9, 10a-d, 11a-e, and 12a-i in
high yield and purities (see Tables 4-6).
Acknowledgment. This investigation was generously sup-
ported by partial funds provided the National Institutes of Health
(KU Center of Excellence for Chemical Methodologies and
Library Development, 1P50 GM069663) with additional funds
from the State of Kansas and NIGMS P41 GM076302. The
authors thank Materia, Inc., for supplying catalyst and helpful
discussions.
1
Supporting Information Available: Tabulated H NMR and
mass data of crude products 8-12 obtained by the described
successful benzylation method; 1H NMR and 13C NMR spectra of
1
intermediates 2-5, H NMR spectra of 8-12. This material is
7a (XdH, n ) 50): 5a (2.00 g, 5.83 mmol) and catalyst 6 (99
mg, 0.117 mmol) in CH2Cl2 (60 mL) was refluxed for 3.5 h to
give 1.98 g of light-brown free-flowing solid (98%).
available free of charge via the Internet at http://acs.pubs.org.
JO0620260
3198 J. Org. Chem., Vol. 72, No. 9, 2007